Abstract

Calcium (Ca(2+)) is an important second messenger and has been the subject of numerous experimental measurements and mechanistic studies in intracellular signaling. Calcium profile can also serve as a useful cellular phenotype. Kinetic models of calcium dynamics provide quantitative insights into the calcium signaling networks. We report here the development of a complex kinetic model for calcium dynamics in RAW 264.7 cells stimulated by the C5a ligand. The model is developed using the vast number of measurements of in vivo calcium dynamics carried out in the Alliance for Cellular Signaling (AfCS) Laboratories. Ligand binding, phospholipase C-beta (PLC-beta) activation, inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R) dynamics, and calcium exchange with mitochondria and extracellular matrix have all been incorporated into the model. The experimental data include data from both native and knockdown cell lines. Subpopulational variability in measurements is addressed by allowing nonkinetic parameters to vary across datasets. The model predicts temporal response of Ca(2+) concentration for various doses of C5a under different initial conditions. The optimized parameters for IP(3)R dynamics are in agreement with the legacy data. Further, the half-maximal effect concentration of C5a and the predicted dose response are comparable to those seen in AfCS measurements. Sensitivity analysis shows that the model is robust to parametric perturbations.